The proposed study will evaluate changes in antithrombin III (AT III) catabolism in man and changes manifested by a decreased ability of this coagulation inhibitor to neutralize coagulation enzymes and/or to react with heparin. Such changes in AT III are potentially associated with enhancement of the pathway leading to thrombosis. Catabolism of AT III will be investigated using AT III prepared for clinical trials by American Red Cross. This AT III preparation will be labelled with 125I and injected into control subjects and patients treated with heparin for various periods of time. Heparin given continuously to a patient causes a major reduction in circulating AT III through an unknown mechanism. By comparing the rate of 125I AT III decrease with changes in endogenous AT III levels in patients we will evaluate whether AT III turnover is uniformly enhanced throughout all stages of heparin therapy and estimate the kinetics of biodegradation of AT III prepared for use in human subjects. The data obtained will be relevant to AT III metabolism in general, to the mechanism of heparin-induced reduction of AT III in vivo, and to clinical usage of AT III concentrates. The second part of study will focus on altered in vitro forms of AT III. Uncomplexed AT III that shows decreased or abolished binding properties appears in the process of AT III purification and is created in the reaction of AT III with thrombin via limited proteolysis. We will attempt to find the conditions required and most favorable for production of such modified AT III derivatives, to isolate and purify these derivatives, and to study their immunologic, functional and structural properties. The data obtained should contribute evidence pertinent to the nature and origin of the aberrant AT III present in small amounts in normal human plasma and should be helpful for detection of both laboratory markers of thrombosis and genetic variants of AT III.